US4418205A - 16-Amino-18,19,20-trinor-prostaglandin derivatives, and acid addition salts - Google Patents

16-Amino-18,19,20-trinor-prostaglandin derivatives, and acid addition salts Download PDF

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Publication number
US4418205A
US4418205A US06/329,039 US32903981A US4418205A US 4418205 A US4418205 A US 4418205A US 32903981 A US32903981 A US 32903981A US 4418205 A US4418205 A US 4418205A
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trinor
trans
cis
phenyl
amino
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Eva Toth-Sarudy
Gabor Ambrus
Gyorgy Cseh
Janos Borvendeg
Imre Moravcsik
Gabriella Mezei
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Patentbureau Danubia
Teva Hungary Pharmaceutical Marketing PLC
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Patentbureau Danubia
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Assigned to GYOGYSZERKUTATO INTEZET reassignment GYOGYSZERKUTATO INTEZET ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: AMBRUS, GABOR, BORVENDEG, JANOS, CSEH, GYORGY, MEZEI, GABRIELLA, MORAVCSIK, IMRE, TOTH-SARUDY, EVA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to new 16-amino-18,19,20-trinor-prostaglandin derivatives of general formula I ##STR1## having at C-17 a substituted or unsubstituted phenyl group, wherein C-15 and C-16 may have either S or R configuration, Y stands for a hydrogen atom or a lower alkyl group, W for a hydrogen atom, halogen atom, hydroxy group, lower alkyl or alkoxy group, and their acid addition salts. Furthermore, the invention relates to a process for the preparation of these compounds.
  • Drug research aims to utilize the physiological activity of prostaglandins in diverse fields of therapy.
  • Natural prostaglandins possess the unfavourable property of exhibiting simultaneously a wide range of activity, furthermore they are rapidly decomposed by the organisms. These disadvantages may be eliminated by preparing prostaglandin analogues which are metabolized at a lower rate, and which possess a more selective activity /P. Ramwell and I. Saw: Ann. N.Y. Acad. Sci. 180, 10 /1971//.
  • the invention relates to novel prostaglandin derivatives which have a 1-amino-2-phenyl-ethyl group optionally substituted by a halogen, hydroxy, alkyl or alkoxy group, instead of the n-amyl group forming the C-16 to C-20 fragment of natural prostaglandins, and a process for the preparation thereof.
  • the new 16-amino-18,19,20-trinor-prostaglandin derivatives of general formula I having at C-17 a substituted or unsubstituted phenyl group, wherein C-15 and C-16 may have either S or R configuration, Y stands for a hydrogen atom or a lower alkyl group, W for a hydrogen atom, halogen atom, hydroxy group, lower alkyl or alkoxy group, and their acid addition salts, can be prepared by removing the ester group and the p-nitrobenzyloxycarbonyl protective group of a 9 ⁇ ,11 ⁇ ,15-trihydroxy-16-p-nitrobenzyloxycarbonylamido-17-phenyl-5-cis,13-trans-18,19,20-trinor-prostadienoic acid derivative of the general formula XII ##STR2## wherein C-15 and C-16 may have either S or R configuration, W is specified as above, and Y stands for a lower alkyl group, in an optional
  • the isolated product can be converted into an acid addition salt by methods known per se.
  • the Zn dust reduction in acetic acid is carried out within a temperature range of -5° C. to +10° C., preferably at 0° C., the ester hydrolysis between 0° C. to +10° C., preferably at +5° C.
  • the p-nitrobenzyloxycarbonyl protective group of a compound of general formula XII can be removed by catalytic transfer hydrogenation in the presence of a PD-C catalyst and cyclohexadiene.
  • ester hydrolysis can advantageously be carried out by means of esterase enzymes such as Rhizopus orizae lipase /Hungarian Patent No. 160,109/.
  • esterase enzymes such as Rhizopus orizae lipase /Hungarian Patent No. 160,109/.
  • sequence of the removal of the p-nitrobenzyloxycarbonyl protective group and the ester group may be interchanged.
  • a compound of general formula I possessing a free amino group, and obtained by the removal of the p-nitrobenzyloxycarbonyl protective group, and optionally by the cleavage of the ester group, is preferably reacted in solution with an inorganic or organic acid, or eventually with the solution thereof in a suitable solvent, and the acid addition salt formed is separated by methods known per se.
  • the 1 ⁇ -/6-carbalkoxy-2-hexenyl/-2 ⁇ -formyl-cyclopentane-3 ⁇ ,5.alpha.-diol-diacylates are preferred starting materials for preparing prostaglandin derivatives modified in their 3-hydroxy-1-trans-octenyl side chain, as these intermediary substances, being in the final stage of prostaglandin synthesis can be easily converted into various prostaglandin analogues by suitably varying the Wittig-reagent utilized for side-chain formation.
  • the Wittig-reagents required for preparing the prostaglandin derivatives of the present invention can be prepared from either S- or R-phenylalanine, or from phenylalanine derivatives substituted by a halogen atom, hydroxy, alkyl or alkoxy group in the benzene nucleus according to the following reaction scheme:
  • the p-nitrobenzyloxycarbonyl-S-phenylalanine is transformed in tetrahydrofuran, in the presence of N-methylmorpholine by the addition of a molar amount of isobutyl chloroformate at -15° C. into a mixed anhydride derivative.
  • N-methylmorpholine hydrochloride is precipitated.
  • An excess of a solution of diazomethane in ether is added dropwise to this precipitated mixture, and stirred for 3 hours at -15° C.
  • dry hydrogen chloride is led into the mixture containing the diazoketone derivative, formed upon the reaction with diazomethane, at -15° C. to obtain the 1-chloro-2-oxo-3/S/-p-nitrobenzyloxycarbonylamido-4-phenyl-butane.
  • the 1-chloro-2-oxo-3/S/-p-nitrobenzyloxycarbonylamido-4-phenyl-butane is reacted in ether at boiling temperature with tri-n-butyl-phosphine or triphenyl-phosphine, resp.
  • the phosphorane derivatives, utilized as Wittig reagents, are set free from the resulting phosphonium salts by the addition of the solution of an alkali metal hydroxide.
  • the 9 ⁇ ,11 ⁇ -diacyloxy-15-oxo-16/S/-p-nitrobenzyloxycarbonylamido-17-phenyl-5-cis,13-trans-18,19,20-trinor-prostandienoic acid alkyl ester derivative, formed in the course of the reaction, is separated from the tri-n-butyl-phosphine oxide, also formed in the reaction, and from the residual excess of tri-n-butyl-2-oxo-3/S/-p-nitrobenzyloxycarbonylamido-4-phenyl-butylidene-phosphorane preferably by chromatography carried out on a silica gel column.
  • test material was administered subcutaneously to mice being in the 16th to 17th day of their pregnancy /3rd consortium/, then the number of abortions ensuing with 48 hours was registered, as well as the live and dead fetuses following the removal of the uterus, and the scars on the placenta.
  • the new compound exhibits a 13 fold potency compared to PGF 2 ⁇ , and an 8 fold potency compared to PGF 2 ⁇ methyl ester.
  • organs were suspended in isotonic salt solution in a constant oxygen flow. It was found that the ileum of the mouse, rat and guinea pig, furthermore the bronchial and uterine muscles of the guinea pig are relatively insensitive to the new derivatives. In agreement with this the minimal dose inducing uterus contraction in the mouse, hamster and rat is larger by 1 to 2 orders of magnitude than in the case of PGF 2 ⁇ .
  • the metabolic stability of the new derivatives is also playing a major role in the excellent biological potency of the compounds: prostaglandin-15-hydroxy-dehydrogenase, isolated from the lung, and being the most active inactivating enzyme of natural prostaglandins, fails to oxidize the 16-amino-17-phenyl-18,19,20-trinor-prostaglandin derivatives. Furthermore the new derivatives do not inhibit the enzymatic oxidation of PGF 2 ⁇ either /test system: P. Tolnay et al.: Acta Biochim. Biophys. Acad. Sci. Hung. 14, 67 /1979//.
  • the 9 ⁇ ,11 ⁇ ,15/ ⁇ /-trihydroxy-16-amino-17-phenyl-5-cis,13-trans-18,19,20-trinor-prostadienic acid derivatives of the invention can be converted into pharmaceutical compositions by usual methods applied in drug processing /it is especially advantageous to prepare injections/.
  • These formulations may find application primarily in cattle raising for estrus and birth synchronization, furthermore in the veterinary praxis for the treatment of sterility, chronic endometritis, or pyometry.
  • the starting materials of Examples 1 and 2 can be prepared according to the following process:
  • Tri-n-butylphosphine /5.4 ml, 0.022 mole/ is added under stirring to a solution of 1-chloro-2-oxo-3/S/-p-nitrobenzyloxycarbonylamido-4-phenyl-butane /7.5 g, 0.02 mole/ in dichloromethane /100 ml/.
  • the reaction mixture is heated to 60° C. for 2 hours, then is evaporated to dryness under reduced pressure. Water /50 ml/ is poured over the residue, and the unreacted tri-n-butylphosphine is extracted three times with n-heptane /20 ml/.
  • Diethylether /20 ml/ is added to the aqueous layer containing the tri-n-butyl-2-oxo-3/S/-p-nitrobenzyloxycarbonylamido-4-phenyl-butyl-phosphonium chloride, and 2 N sodium hydroxide is added dropwise /10 ml/ under cooling /5° C./, then the reaction mixture is stirred for 6 minutes. Then the aqueous layer is separated and extracted with ether /20 ml/. The combined ethereal extracts are dried over Klinosorb-4 /Reanal, Budapest/.
  • reaction mixture is stirred under nitrogen at room temperature for 36 hours, then it is poured into a 1 M solution of disodium hydrogen phosphate /210 ml/ /pH 6/, and extracted three times with ethyl acetate /100 ml/.
  • the combined ethyl acetate extracts are evaporated at reduced pressure, and the residue submitted to chromatography applying silica gel as adsorbent /100 g, Kieselgel 40, Reanal, Budapest/, and a mixture of n-hexane-ethyl acetate, containing gradually increasing amounts of ethyl acetate, as developing solvent.
  • the reaction mixture is stirred under nitrogen at 0° C. for 16 hours, then the pH of the solution is adjusted with 8 percent aqueous oxalic acid solution to 5.5.
  • the methanol is evaporated at reduced pressure and 5° C., and the residual aqueous solution freeze-dried.
  • the dry residue is submitted to chromatography on a silica gel column /10 g/, Kieselgel 40, Reanal, Budapest/ with a solvent system of chloroform-methanol, containing gradually increasing amounts of methanol.
  • the product is eluted from the column with chloroform containing 20 percent of methanol.
  • reaction mixture is diluted with dichloromethane /20 ml/, the Zn dust filtered off, and the filtrate evaporated at reduced pressure.
  • the residue is submitted to chromatography on a column prepared from silica gel /5 g/, in a system of chloroform-methanol containing gradually increasing amounts of methanol.
  • the product itself is eluted from the column with a mixture containing 20% of methanol. Yield: 101 mg /50%/ of 9 ⁇ ,11 ⁇ ,15/ ⁇ /-trihydroxy-16/S/-amino-17-phenyl-5-cis,13-trans-18,19,20-trinor-prostadienoic acid /isomer A/.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US06/329,039 1980-12-09 1981-12-09 16-Amino-18,19,20-trinor-prostaglandin derivatives, and acid addition salts Expired - Fee Related US4418205A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU2941/80 1980-12-09
HU8029410A HU184356B (en) 1980-12-09 1980-12-09 Process for preparing new 16-amino-prostaglandin derivatives and acid addition salts thereof

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US (1) US4418205A (fr)
JP (1) JPS57171963A (fr)
AT (1) AT377976B (fr)
AU (1) AU542710B2 (fr)
BE (1) BE891348A (fr)
CA (1) CA1163586A (fr)
CH (1) CH648298A5 (fr)
CS (1) CS223897B2 (fr)
DD (1) DD208149A5 (fr)
DE (1) DE3148752A1 (fr)
DK (1) DK540881A (fr)
FI (1) FI70885C (fr)
FR (1) FR2495611A1 (fr)
GB (1) GB2090829B (fr)
GR (1) GR76966B (fr)
HU (1) HU184356B (fr)
IL (1) IL64488A (fr)
IT (1) IT1211144B (fr)
NL (1) NL8105507A (fr)
SE (1) SE441674B (fr)

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* Cited by examiner, † Cited by third party
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JPS5975273U (ja) * 1983-02-03 1984-05-22 三洋電機株式会社 洗濯機の溢水々位調節装置

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BE863116A (fr) * 1978-01-20 1978-05-16 Chinoin Gyogyszer Es Vegyeszet Nouveaux derives 17-aza-pgf2alpha, procede permettant de les preparer et compositions pharmaceutiques qui les contiennent.

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Derwent Abstract 13442W/08, J4 9109-341, 02-26-73. *
Derwent Abstract 26295W/16, FR 2235-927, 06-25-73. *
Derwent Abstract 38572A/22, BE 863-116, 01-20-78. *
Derwent Abstract 94831X/51, J5 1125-046, 11-22-74. *

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IT1211144B (it) 1989-09-29
GB2090829B (en) 1984-06-27
FI70885B (fi) 1986-07-18
SE441674B (sv) 1985-10-28
NL8105507A (nl) 1982-07-01
FR2495611A1 (fr) 1982-06-11
BE891348A (fr) 1982-06-04
DD208149A5 (de) 1984-03-28
FR2495611B1 (fr) 1983-12-09
CA1163586A (fr) 1984-03-13
SE8107347L (sv) 1982-06-10
DE3148752A1 (de) 1982-08-19
FI813938L (fi) 1982-06-10
IL64488A0 (en) 1982-03-31
GB2090829A (en) 1982-07-21
HU184356B (en) 1984-08-28
DK540881A (da) 1982-06-10
CS223897B2 (en) 1983-11-25
JPS57171963A (en) 1982-10-22
CH648298A5 (de) 1985-03-15
AU542710B2 (en) 1985-03-07
ATA524181A (de) 1984-10-15
IT8125485A0 (it) 1981-12-09
IL64488A (en) 1985-03-31
GR76966B (fr) 1984-09-04
FI70885C (fi) 1986-10-27
AT377976B (de) 1985-05-28
AU7836381A (en) 1982-06-17

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